Gfi-1/MEL-18/HDAC通路在长春新碱诱导的神经病理性疼痛中的作用研究

化疗药物如长春新碱（VCR）能够导致周围神经病变引起神经病理性疼痛（CINP），但机制尚未十分明确。MEL-18是多梳蛋白家族成员，在胚胎形成、细胞分化和增殖中发挥重要作用。我们的前期研究发现在VCR诱导的CINP模型中MEL-18的表达显著升高，干扰MEL-18表达能够提高机械痛阈值，而过表达MEL-18则降低机械痛阈值。此外，已有研究证明HDAC参与疼痛反应，我们在CINP模型中也观察到MEL-18能够正性调节下游HDAC的表达水平，提示VCR通过MEL-18/HDAC介导CINP。进一步生物信息学分析发现，转录因子Gfi-1在MEL-18启动子区有结合位点，沉默Gfi-1后，MEL-18的转录水平受到抑制。故推测：VCR通过Gfi-1调控MEL-18表达，进而升高HDAC诱发CINP。本课题将在动物、细胞和分子水平深入研究这一通路在CINP中的作用，为临床治疗提供理论依据。

Chemotherapeutic drugs such as vincristine (VCR) which can cause peripheral neuropathy, characterized by neuropathic pain, as well as sensory and motor dysfunction. However, the underlying mechanism is still unclear. Emerging evidence supports epigenetic mechanisms to the development or maintenance of neuropathic pain states. Melanoma nuclear protein-18 (MEL-18) gene is one of the core members of the polycomb group family, which plays an important role in embryogenesis, cell growth and proliferation, and self-renewal of stem cells. The previous findings of the applicant revealed that: 1) MEL-18 was highly expressed in the VCR-induced neuropathic pain (CINP) induced in infant mice and adult mice model; 2) Interfering with MEL-18 expression can improve the mechanical withdrawal threshold, while the over-expression of MEL-18 reduces the mechanical withdrawal threshold; 3) Moreover, previous studies have shown that HDAC involves in pain events, and we observed in the CINP model that MEL-18 can regulate the expression level of HDAC downstream, suggesting that MEL-18/HDAC may involve in the pathogenic pathway of VCR-induced CINP; 4) bioinformatics analysis showed binding sites of transcription factor Gfi-1 in MEL-18 promoter region. Based on these findings and facts, we hypothesize that Gfi-1-regulated MEL-18 might mediate VCR-induced CINP via promoting the expression of HDAC. In the present project, we will fully investigate the contribution of this pathway in VCR -induced CINP through employing various in vitro and in vivo methods including animal, cell and molecule models. The study will also offer new insights into the potential therapy of VCR -induced CINP.